tbuckley/cabot-search huggingface dataset:
Whole-genome sequencing reveals the genetic mechanisms of domestication in classical inbred mice
Authors: Ming Liu, Caixia Yu, Zhichao Zhang, Mingjing Song, Xiuping Sun, Jaroslav Piálek, Jens Jacob, Jiqi Lu, Lin Cong, Hongmao Zhang, Yong Wang, Guoliang Li, Zhiyong Feng, Zhenglin Du, Meng Wang, Xinru Wan, Dawei Wang, Yan-Ling Wang, Hongjun Li, Zuoxin Wang, Bing Zhang, Zhibin Zhang
Journal: Genome biology (2022)

Abstract Background The laboratory mouse was domesticated from the wild house mouse. Understanding the genetics underlying domestication in laboratory mice, especially in the widely used classical inbred mice, is vital for studies using mouse models. However, the genetic mechanism of laboratory mouse domestication remains unknown due to lack of adequate genomic sequences of wild mice. Results We analyze the genetic relationships by whole-genome resequencing of 36 wild mice and 36 inbred strains. All classical inbred mice cluster together distinctly from wild and wild-derived inbred mice. Using nucleotide diversity analysis, Fst, and XP-CLR, we identify 339 positively selected genes that are closely associated with nervous system function. Approximately one third of these positively selected genes are highly expressed in brain tissues, and genetic mouse models of 125 genes in the positively selected genes exhibit abnormal behavioral or nervous system phenotypes. These positively selected genes show a higher ratio of differential expression between wild and classical inbred mice compared with all genes, especially in the hippocampus and frontal lobe. Using a mutant mouse model, we find that the SNP rs27900929 (T&gt;C) in gene Astn2 significantly reduces the tameness of mice and modifies the ratio of the two Astn2 (a/b) isoforms. Conclusion Our study indicates that classical inbred mice experienced high selection pressure during domestication under laboratory conditions. The analysis shows the positively selected genes are closely associated with behavior and the nervous system in mice. Tameness may be related to the Astn2 mutation and regulated by the ratio of the two Astn2 (a/b) isoforms.
Lingering cardiac involvement in previously well people after mild COVID-19
Journal: Nature Medicine (2022)

Lingering cardiac involvement in previously well people after mild COVID-19Serial heart MRI scans conducted in previously well people with mild initial COVID-19 illness suggest that lingering cardiac symptoms may be explained, at least in part, by ongoing mild cardiac inflammation. The problemLingering cardiac symptoms, including exercise intolerance, tachycardia and chest pain, are increasingly recognized as post-acute COVID-19 sequelae 1 .In patients with a severe course of initial illness, accrued cardiac injury and pre-existing conditions readily explain cardiac symptoms.However, signs of cardiac injury such as elevated troponin levels and structural heart disease are rare in previously well people with mild initial illness, despite often profound cardiac symptoms.Previous studies in populations of mainly young, athletic people have shown subtle non-ischemic cardiac inflammatory changes shortly after initial COVID-19 illness.However, it remains unclear whether these early observations are related to symptoms or persist with time.
TIGIT is the central player in T-cell suppression associated with CAR T-cell relapse in mantle cell lymphoma
Authors: Vivian Changying Jiang, Dapeng Hao, Preetesh Jain, Yijing Li, Qingsong Cai, Yixin Yao, Lei Nie, Yang Liu, Jingling Jin, Wei Wang, Heng-Huan Lee, Yuxuan Che, Enyu Dai, Guangchun Han, Ruiping Wang, Kunal Rai, Andrew Futreal, Christopher Flowers, Linghua Wang, Michael Wang
Journal: Molecular Cancer (2022)

Abstract Background Chimeric antigen receptor (CAR) T-cell therapy using brexucabtagene autoleucel (BA) induces remission in many patients with mantle cell lymphoma (MCL), and BA is the only CAR T-cell therapy approved by the FDA for MCL. However, development of relapses to BA is recognized with poor patient outcomes. Multiple CAR T-cell therapies have been approved for other lymphomas and the resistance mechanisms have been investigated. However, the mechanisms underlying BA relapse in MCL have not been investigated and whether any previously reported resistance mechanisms apply to BA-relapsed patients with MCL is unknown. Methods To interrogate BA resistance mechanisms in MCL, we performed single-cell RNA sequencing on 39 longitudinally collected samples from 15 BA-treated patients, and multiplex cytokine profiling on 80 serial samples from 20 patients. Results We demonstrate that after BA relapse, the proportion of T cells, especially cytotoxic T cells (CTLs), decreased among non-tumor cells, while the proportion of myeloid cells correspondingly increased. TIGIT , LAG3 , and CD96 were the predominant checkpoint molecules expressed on exhausted T cells and CTLs; only TIGIT was significantly increased after relapse. CTLs expanded during remission, and then contracted during relapse with upregulated TIGIT expression. Tumor cells also acquired TIGIT expression after relapse, leading to the enhanced interaction of tumor cell TIGIT with monocyte CD155/PVR. In myeloid cells, post-relapse HLA-II expression was reduced relative to pretreatment and during remission. Myeloid-derived suppressor cells (MDSCs) were enriched after relapse with elevated expression of activation markers, including CLU (clusterin) and VCAN (versican). Extracellular chemokines (CCL4, CXCL9, CXCL13), soluble checkpoint inhibitors (sPD-L1, sTIM3, s4-1BB), and soluble receptors (sIL-2R, sTNFRII) were decreased during remission but elevated after relapse. Conclusions Our data demonstrate that multiple tumor-intrinsic and -extrinsic factors are associated with T-cell suppression and BA relapse. Among these, TIGIT appears to be the central player given its elevated expression after BA relapse in not only CTLs but also MCL cells. The acquisition of TIGIT expression on tumor cells is MCL-specific and has not been reported in other CAR T-treated diseases. Together, our data suggest that co-targeting TIGIT may prevent CAR T relapses and thus promote long-term progression-free survival in MCL patients.
Galectin-3 Inhibition in COVID-19
Authors: Kiran Reddy, Alistair Nichol, Daniel F. McAuley
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Galectin-3 Inhibition in COVID-19Galectins have emerged as molecules that are involved in many immune processes, including neutrophil migration, cytokine release, and the control of T and B cell death (1).Galectin-3, in particular, is highly expressed in monocytes, macrophages, neutrophils, fibroblasts, epithelial cells, and endothelial cells and is secreted in response to inflammatory stimuli (2), potentially amplifying the host inflammatory response during infection (3).It is a marker of severity in acute respiratory distress syndrome (ARDS) not related to coronavirus disease (COVID-19) (4) and has also been recently proposed as a biomarker for COVID-19 severity (5).Galectin-3 stimulates the release of IL-1, IL-6, and tumor necrosis factor alpha (6), which are considered to be important in the pathogenesis of severe COVID-19.A specific galectin-3 inhibitor may have the
Consultant who claimed for shifts covered by his salary is struck off
Authors: Clare Dyer
Journal: BMJ (2022)

<h3>Abstract</h3> Nahal Rahaf 2 (NR2) is an Early Upper Paleolithic (ca. 35 kya) rock shelter in the southern Judean Desert in Israel. Two excavation seasons in 2019 and 2020 revealed a stratigraphical sequence composed of intact archaeological surfaces attributed to the ‘Arkov-Divshon’ cultural entity of the arid southern Levant. We present the faunal assemblages from the site, which are rare among the desert sites due to preservation problems. Our results suggest that the residents of the site exploited d prime adult caprines (<i>Capra</i> cf. <i>Capra ibex</i>), but were also engaged in hunting of gazelles (<i>Gazella</i> cf. <i>Gazella gazella</i>), whose carcasses were selectively transported to the site and processed for within-bone nutrients. Long-range hunting trips are suggested by the body-part selection in relatively small bovids, and by the presence of species representing wetter habitat patches 20-30 km north of the site. The bi-focal emphasis on generalized gazelle and age-specific caprine hunting, is unique among Late Pleistocene sites from the Levant. The proportion of caprines increases through the stratigraphic sequence, suggesting more specialized economy through time and in inverse relations to site use intensity.
Doctors should screen Americans under 65 for anxiety, draft guidelines say
Authors: Janice Hopkins Tanne
Journal: BMJ (2022)

One-hundred and four infants with congenital heart disease were identified from their birth certificates and matched with normal controls. Their gestational histories were examined to see whether they had been exposed to exogenous sex hormones. Exposure was 8-5 times more common among the infants with malformations than among controls. A history of hormone exposure was more common among those patients with multiple malformations, and the exposed infants were also more likely to have died (and to have died earlier) than those who had not been exposed, which suggests that hormone exposure causes severe types of malformations. The commonest type of exposure was to hormone pregnancy tests, which was needless exposure. Only two of the mothers of malformed infants had inadvertently used oral contraceptives in the first trimester.
Intratumoral Therapy to Make a “Cold” Tumor “Hot”: The Jury Is Still Out
Authors: Salman R. Punekar, Jeffrey S. Weber
Journal: Clinical Cancer Research (2022)

Tilsotolimod, an oligodeoxynucleotide TLR9 agonist, administered intratumorally, has been clinically evaluated. This compound has demonstrated the ability to induce changes within the tumor microenvironment, to convert noninflamed cold tumors into inflamed hot tumors, with the hope that these tumors will be more responsive to immune checkpoint blockade. See related article by Babiker et al., p. 5079
Transient Systemic Autophagy Inhibition Is Selectively and Irreversibly Deleterious to Lung Cancer
Authors: Khoosheh Khayati, Vrushank Bhatt, Taijin Lan, Fawzi Alogaili, Wenping Wang, Enrique Lopez, Zhixian Sherrie Hu, Samantha Gokhale, Liam Cassidy, Masashi Narita, Ping Xie, Eileen White, Jessie Yanxiang Guo
Journal: Cancer Research (2022)

Abstract Autophagy is a conserved catabolic process that maintains cellular homeostasis. Autophagy supports lung tumorigenesis and is a potential therapeutic target in lung cancer. A better understanding of the importance of tumor cell-autonomous versus systemic autophagy in lung cancer could facilitate clinical translation of autophagy inhibition. Here, we exploited inducible expression of Atg5 shRNA to temporally control Atg5 levels and to generate reversible tumor-specific and systemic autophagy loss mouse models of KrasG12D/+;p53−/− (KP) non–small cell lung cancer (NSCLC). Transient suppression of systemic but not tumor Atg5 expression significantly reduced established KP lung tumor growth without damaging normal tissues. In vivo13C isotope tracing and metabolic flux analyses demonstrated that systemic Atg5 knockdown specifically led to reduced glucose and lactate uptake. As a result, carbon flux from glucose and lactate to major metabolic pathways, including the tricarboxylic acid cycle, glycolysis, and serine biosynthesis, was significantly reduced in KP NSCLC following systemic autophagy loss. Furthermore, systemic Atg5 knockdown increased tumor T-cell infiltration, leading to T-cell-mediated tumor killing. Importantly, intermittent transient systemic Atg5 knockdown, which resembles what would occur during autophagy inhibition for cancer therapy, significantly prolonged lifespan of KP lung tumor-bearing mice, resulting in recovery of normal tissues but not tumors. Thus, systemic autophagy supports the growth of established lung tumors by promoting immune evasion and sustaining cancer cell metabolism for energy production and biosynthesis, and the inability of tumors to recover from loss of autophagy provides further proof of concept that inhibition of autophagy is a valid approach to cancer therapy. Significance: Transient loss of systemic autophagy causes irreversible damage to tumors by suppressing cancer cell metabolism and promoting antitumor immunity, supporting autophagy inhibition as a rational strategy for treating lung cancer. See related commentary by Gan, p. 4322
Prescription Patterns of Cardiovascular- and Kidney-Protective Therapies Among Patients With Type 2 Diabetes and Chronic Kidney Disease
Authors: Julio A. Lamprea-Montealegre, Erin Madden, Sri Lekha Tummalapalli, Chi D. Chu, Carmen A. Peralta, Yuxian Du, Rakesh Singh, Sheldon X. Kong, Delphine S. Tuot, Michael G. Shlipak, Michelle M. Estrella
Journal: Diabetes Care (2022)

To assess the prevalence and correlates of prescription of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and/or glucagon-like peptide 1 receptor agonists (GLP1-RA) in individuals with type 2 diabetes mellitus (T2DM) with and without chronic kidney disease (CKD).This was a cross-sectional analyses of SGLT2i and GLP1-RA prescriptions from 1 January 2019 to 31 December 2020 in the Veterans Health Administration System. The likelihood of prescriptions was examined by the presence or absence of CKD and by predicted risks of atherosclerotic cardiovascular disease (ASCVD) and end-stage kidney disease (ESKD).Of 1,197,880 adults with T2DM, SGLT2i and GLP1-RA were prescribed to 11% and 8% of patients overall, and to 12% and 10% of those with concomitant CKD, respectively. In adjusted models, patients with severe albuminuria were less likely to be prescribed SGLT2i or GLP1-RA versus nonalbuminuric patients with CKD, with odds ratios (ORs) of 0.91 (95% CI 0.89, 0.93) and 0.97 (0.94, 1.00), respectively. Patients with a 10-year ASCVD risk >20% (vs. <5%), had lower odds of SGLT2i use (OR 0.66 [0.61, 0.71]) and GLP1-RA prescription (OR 0.55 [0.52, 0.59]). A 5-year ESKD risk >5%, compared with <1%, was associated with lower likelihood of SGLT2i prescription (OR 0.63 [0.59, 0.67]) but higher likelihood of GLP1-RA prescription (OR 1.53 [1.46, 1.61]).Among a large cohort of patients with T2DM, prescription of SGLT2i and GLP1-RA was low in those with CKD. We observed a "risk-treatment paradox," whereby patients with higher risk of adverse outcomes were less likely to receive these therapies.
GABA facilitates spike propagation through branch points of sensory axons in the spinal cord
Authors: Krishnapriya Hari, Ana M. Lucas-Osma, Krista Metz, Shihao Lin, Noah Pardell, David A. Roszko, Sophie Black, Anna Minarik, Rahul Singla, Marilee J. Stephens, Robert A. Pearce, Karim Fouad, Kelvin E. Jones, Monica A. Gorassini, Keith K. Fenrich, Yaqing Li, David J. Bennett
Journal: Nature Neuroscience (2022)
Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups
Authors: Manuel Mattheisen, Jakob Grove, Thomas D. Als, Joanna Martin, Georgios Voloudakis, Sandra Meier, Ditte Demontis, Jaroslav Bendl, Raymond Walters, Caitlin E. Carey, Anders Rosengren, Nora I. Strom, Mads Engel Hauberg, Biao Zeng, Gabriel Hoffman, Wen Zhang, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Esben Agerbo, Bru Cormand, Merete Nordentoft, Thomas Werge, Ole Mors, David M. Hougaard, Joseph D. Buxbaum, Stephen V. Faraone, Barbara Franke, Søren Dalsgaard, Preben B. Mortensen, Elise B. Robinson, Panos Roussos, Benjamin M. Neale, Mark J. Daly, Anders D. Børglum
Journal: Nature Genetics (2022)
Population-level variation in enhancer expression identifies disease mechanisms in the human brain
Authors: Pengfei Dong, Gabriel E. Hoffman, Pasha Apontes, Jaroslav Bendl, Samir Rahman, Michael B. Fernando, Biao Zeng, James M. Vicari, Wen Zhang, Kiran Girdhar, Kayla G. Townsley, Ruth Misir, Andrew Chess, Attila Gulyás-Kovács, Bibi Kassim, Eva Xia, Joseph D. Buxbaum, Laura Sloofman, Lizette Couto, Mariana Amaro, Marina Iskhakova, Michael Breen, Olivia Devillers, Schahram Akbarian, Shan Jiang, Steven P. Kleopoulos, Yixian Ma, Yungil Kim, Sabina Berretta, Ajeet Mandal, Barbara K. Lipska, Francis McMahon, Pavan K. Auluck, Stefano Marenco, Kelsey S. Montgomery, Mette A. Peters, Solveig K. Sieberts, Chang-Gyu Hahn, Raquel Gur, Jiebiao Wang, Bernie Devlin, David A. Lewis, Lambertus Klei, Enrico Domenici, Michele Filosi, Roberto Visintainer, Douglas M. Ruderfer, Lide Han, Kristen J. Brennand, Vahram Haroutunian, Georgios Voloudakis, John F. Fullard, Panos Roussos
Journal: Nature Genetics (2022)
A Bill of Children’s Digital Rights Is Required to Improve and Sustain Children’s Futures Globally
Authors: Andres Roman-Urrestarazu, Jane Kinsey, Robin van Kessel
Journal: JAMA Pediatrics (2022)

This Viewpoint calls for policy action, such as a comprehensive Bill of Children’s Digital Rights, that would embrace rights allowing children and young people to access the digital infrastructure and interact with digital media safely.
General Anesthesia vs Conscious Sedation for Endovascular Treatment in Patients With Posterior Circulation Acute Ischemic Stroke
Authors: Fa Liang, Youxuan Wu, Xinyan Wang, Li Yan, Song Zhang, Minyu Jian, Haiyang Liu, Anxin Wang, Fan Wang, Ruquan Han, Matthew TV Chan, Zhongrong Miao, Xiaochuan Huo, Yuming Peng, Guoming Li, Yang Zhou, Yang Bai, Xiuheng Li, Xiang Yan, Wanning Yang, Xinxin Wang, Jiaxin Li, Yan Zhao, Shu Li, Yiming Deng, Dapeng Mo, Ligang Song, Xuan Sun
Journal: JAMA Neurology (2022)

No definitive conclusion can be made on the best choice of anesthesia for people with acute posterior circulation stroke during endovascular treatment. Only a few observational studies have focused on this topic in recent years, and they have differing conclusions. To examine whether conscious sedation (CS) is a feasible alternative to general anesthesia (GA) during endovascular treatment in patients with acute posterior circulation stroke. A randomized parallel-group exploratory trial with blinded end point evaluation (Choice of Anesthesia for Endovascular Treatment of Acute Ischemic Stroke [CANVAS II]) enrolled adult patients from March 2018 to June 2021 at 2 comprehensive care hospitals in China. Patients with acute posterior circulation stroke were enrolled, randomized, and monitored for 3 months. Of 210 patients admitted with acute ischemic posterior circulation stroke, 93 were recruited and 87 were included in the intention-to-treat (ITT) analysis after exclusions, 43 were assigned to GA and 44 to CS. All analyses were unadjusted or adjusted with the ITT principle. Participants were randomly assigned to CS or GA in a 1:1 ratio. The primary end point was functional independence at 90 days evaluated with the modified Rankin Scale (mRS). A total of 87 participants were included in the ITT study (mean [SD] age, 62 [12] years; 16 [18.4%] female and 71 [81.6%] male). Of these, 43 were in the GA group and 44 in the CS group. The overall baseline median (IQR) National Institute of Health Stroke Scale (NIHSS) score was 15 (12-17). In the CS group, 13 people (29.5%) were ultimately transferred to GA. The CS group had a higher incidence of functional independence; however, no significant difference was found between the 2 groups (48.8% vs 54.5%; risk ratio, 0.89; 95% CI, 0.58-1.38; adjusted odds ratio [OR], 0.91; 95% CI, 0.37-2.22). However, GA performed better in successful reperfusion (mTICI 2b-3) under ITT analysis (95.3% vs 77.3%; adjusted OR, 5.86; 95% CI, 1.16-29.53). The findings in this study suggest that CS was not better than GA for the primary outcome of functional recovery and was perhaps worse for the secondary outcome of successful reperfusion. ClinicalTrials.gov Identifier: NCT03317535.
Detection of Messenger RNA COVID-19 Vaccines in Human Breast Milk
Authors: Nazeeh Hanna, Ari Heffes-Doon, Xinhua Lin, Claudia Manzano De Mejia, Bishoy Botros, Ellen Gurzenda, Amrita Nayak
Journal: JAMA Pediatrics (2022)

This cohort study investigates the presence of COVID-19 vaccine mRNA in the expressed breast milk of lactating individuals who received the vaccination within 6 months after delivery.
Development and External Validation of a Mortality Prediction Model for Community-Dwelling Older Adults With Dementia
Authors: W. James Deardorff, Deborah E. Barnes, Sun Y. Jeon, W. John Boscardin, Kenneth M. Langa, Kenneth E. Covinsky, Susan L. Mitchell, Elizabeth L. Whitlock, Alexander K. Smith, Sei J. Lee
Journal: JAMA Internal Medicine (2022)

Importance Estimating mortality risk in older adults with dementia is important for guiding decisions such as cancer screening, treatment of new and chronic medical conditions, and advance care planning. Objective To develop and externally validate a mortality prediction model in community-dwelling older adults with dementia. Design, Setting, and Participants This cohort study included community-dwelling participants (aged ≥65 years) in the Health and Retirement Study (HRS) from 1998 to 2016 (derivation cohort) and National Health and Aging Trends Study (NHATS) from 2011 to 2019 (validation cohort). Exposures Candidate predictors included demographics, behavioral/health factors, functional measures (eg, activities of daily living [ADL] and instrumental activities of daily living [IADL]), and chronic conditions. Main Outcomes and Measures The primary outcome was time to all-cause death. We used Cox proportional hazards regression with backward selection and multiple imputation for model development. Model performance was assessed by discrimination (integrated area under the receiver operating characteristic curve [iAUC]) and calibration (plots of predicted and observed mortality). Results Of 4267 participants with probable dementia in HRS, the mean (SD) age was 82.2 (7.6) years, 2930 (survey-weighted 69.4%) were female, and 785 (survey-weighted 12.1%) identified as Black. Median (IQR) follow-up time was 3.9 (2.0-6.8) years, and 3466 (81.2%) participants died by end of follow-up. The final model included age, sex, body mass index, smoking status, ADL dependency count, IADL difficulty count, difficulty walking several blocks, participation in vigorous physical activity, and chronic conditions (cancer, heart disease, diabetes, lung disease). The optimism-corrected iAUC after bootstrap internal validation was 0.76 (95% CI, 0.75-0.76) with time-specific AUC of 0.73 (95% CI, 0.70-0.75) at 1 year, 0.75 (95% CI, 0.73-0.77) at 5 years, and 0.84 (95% CI, 0.82-0.85) at 10 years. On external validation in NHATS (n = 2404), AUC was 0.73 (95% CI, 0.70-0.76) at 1 year and 0.74 (95% CI, 0.71-0.76) at 5 years. Calibration plots suggested good calibration across the range of predicted risk from 1 to 10 years. Conclusions and Relevance We developed and externally validated a mortality prediction model in community-dwelling older adults with dementia that showed good discrimination and calibration. The mortality risk estimates may help guide discussions regarding treatment decisions and advance care planning.